WO1998038189A1

WO1998038189A1 - Oxazolidines as 5-ht2a-antagonists

Info

Publication number: WO1998038189A1
Application number: PCT/EP1998/000637
Authority: WO
Inventors: Henning Böttcher; Helmut Prücher; Helmut Greiner; Gerd Bartoszyk; Christoph Seyfried
Original assignee: Merck Patent Gmbh
Priority date: 1997-02-26
Filing date: 1998-02-06
Publication date: 1998-09-03
Also published as: AU6394998A; BR9807765A; DK0964863T3; EP0964863B1; DE19707628A1; NO994106L; PL335100A1; RU2196140C2; TW531538B; NO313415B1; KR20000075697A; UA58542C2; CA2281918C; CN1177847C; EP0964863A1; ATE240954T1; JP2009256363A; ES2197466T3; HUP0001093A2; CA2281918A1

Abstract

The invention relates to novel oxazolidine derivatives of formula (I), wherein R?1, R2 and R3¿ have the meaning cited in Claim 1. The invention further relates to the salts thereof and to a method for the production of the inventive compounds. The compounds of formula (I) act as 5-HT¿2A? antagonists having a reuptake-inhibiting, antidepressant or anxiolytic effect and can be used in the production of medicaments.

Description

OXAZOLIDINONE AS 5-HT2A ANTAGONISTS

The invention relates to compounds of the formula

wherein R ^{1 is} H, CN, shark or OA,

R ² , R ³ each independently of one another H, CN, Hai or OA, R ² and R ³ together also methylenedioxy, AH, CF ₃ or alkyl with 1-6 C atoms and

Shark F, Cl, Br, I mean, and their salts.

5 - [(2-oxobenzimidazolin-1-yl) piperidino-methyl] -oxazolidin-2-ones with effects on the central nervous system are e.g. known from EP 0 443 197.

Indole alkyl residues N-alkylated by indole alkyl radicals are e.g. described in EP 0 683 166.

3-phenyl-5 - [(4-RX-piperidino) alkyl] oxazolidin-2-one derivatives, wherein R is phenyl and X is -O-, -S-, -SO- or -SO ₂ - with Effects on the central nervous system are known, for example, from EP 0 635 505. Indole piperidine derivatives with a tricyclic residue and effects on the central nervous system are described, for example, in EP 0 722 942. 4-Aryl-1 - (indane, dihydrobenzofuran or dihydrobenzothiophene-methyl) piperidine derivatives which influence the serotoninergic and dopaminergic transmission and also have a 5-HT reuptake-inhibiting action are described, for example, in WO 95/33721 .

The invention was based on the task of finding new compounds with valuable properties, in particular those which can be used for the production of medicaments. It has been found that the compounds of the formula I and their salts have particularly good pharmacological properties with good tolerability, since they have effects on the central nervous system, in particular dopamine-antagonistic and 5-HT reuptake-inhibiting effects, by using both the affect serotoninergic as well as dopaminergic transmission. In particular, they have affinities for the 5-HT _1A and / or 5-HT _2A receptors.

The compounds of formula I inhibit the binding of tritiated serotonin receptor ligands to hippocampal receptors (Cossery et al., European J. Pharmacol. 140 (1987), 143-155) and inhibit synaptosomal serotonin reuptake (Sherman et al., Life Sci. 23 (1978), 1863-1870). In particular, they bind to δ-HT ^ and D ₂ receptors. There are also changes in DOPA accumulation in the striatum and in the 5-

HTP accumulation in N. graphesauf (Seyfried et al., European J. Pharmacol. 160 (1989), 31-41). The 5-HT _1A antagonistic effect is demonstrated in vitro, for example by inhibiting the 8-OH-DPAT-induced abolition of the electrically induced contraction of the guinea pig ileum (Fozard and Kilbinger, Br. J. Pharmacol. 86 (1985) 601 P). Ex-vivo serves to demonstrate the 5-HT- _A antagonistic effect by inhibiting the 5-HTP accumulation reduced by 8-OH-DPAT (Seyfried et al., European J. Pharmacol. 160 (1989), 31-41). For ex vivo detection of serotonin reuptake inhibition, synaptosomal reuptake inhibition (Wong et al. Neuropsychopharmacol.

8 (1993), 23-33) and p-chloroamphetamine antagonism (Füller et al., J.

Pharmacol. Exp. Ther. 212 (1980), 115-119).

Otherwise, the pharmacological tests can be carried out analogously to the methods described in WO 95/33721.

The compounds of the formula I are therefore suitable both in veterinary medicine and in human medicine for the treatment of functional disorders of the central nervous system. They can be used for the prophylaxis and for combating the consequences of cerebral infarction (apoplexia cerebri) such as stroke and cerebral ischemia, as well as for the treatment of extrapyramidal-motor side effects of neuroleptics and the disease - J -

Parkinson's can be used. However, they are particularly suitable as active pharmaceutical ingredients for anxiolytics, antidepressants, antipsychotics and / or for the treatment of obsessive-compulsive disorder (OCD), anxiety, panic attacks, depression, psychoses, schizophrenia, delusional obsessions, Alzheimer's disease, migraines, Anorexia, sleep disorders, tardive dyskinesias, learning disorders, age-related memory disorders, eating disorders such as bulimia, drug abuse and / or sexual dysfunction.

The compounds of formula I and their physiologically acceptable

Acid addition salts can therefore be used as active pharmaceutical ingredients for anxiolytics, antidepressants, antipsychotics, neuroleptics and / or antihypertonics as well as for positively influencing obsessive-compulsive behavior, eating disorders such as bulimia, tardive dyskinesias, learning disorders and age-related memory disorders.

They can also be used as intermediates for the production of further active pharmaceutical ingredients.

The invention thus relates to the compounds of the formula I and their physiologically acceptable acid addition salts.

The invention accordingly relates to the compounds of the formula I and a process for the preparation of compounds of the formula I, characterized in that

a) a compound of formula II

wherein R ^{1 has} the meaning given in claim 1 and L 01, Br, I or a free or reactive functional group modified OH group,

with a compound of formula III

wherein R j2 and, r R, 3 have the meanings given in claim 1,

implements

or

b) a compound of formula IV

v / orin R ¹ , R ² and R ^{3 have} the meanings given in claim 1,

with a compound of formula V

in which L and L 'each independently mean Cl, Br, I or a free or reactively functionally modified OH group,

implements or

c) a compound of formula VI

in which R ¹ , R ² and R ^{3 have} the meanings given in claim 1,

hydrated,

and / or that a basic compound of formula I is converted into one of its salts by treatment with an acid.

Above and below, the radicals R ¹ , R ² , R ³ and L have the meanings given in the formulas I, II, III, IV and V, unless expressly stated otherwise.

The invention also relates to medicaments of the formula I and their physiologically acceptable salts with 5-HTι _A -, 5-HT2Λ- antagonistic and 5-HT reuptake-inhibiting action.

The invention relates to the compounds of the formula I according to claim 4 and to their enantiomers and their salts.

For all residues that occur several times, such as B. A applies that their meanings are independent of each other.

Alkyl has 1 to 10, preferably 1, 2, 3, 4, 5 or 6 carbon atoms. Alkyl therefore means in particular e.g. Methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1, 1-, 1, 2- or 2,2 -Dimethylpropyl, 1-ethylpropyl, hexyl, 1-,

2-, 3- or 4-methylpentyl, 1, 1-, 1, 2-, 1, 3-, 2,2-, 2,3- or 3,3-dimethyl- butyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1, 1, 2- or 1, 2,2-trimethylpropyl, also also fluoromethyl, difluoromethyl, trifluoromethyl, 1, 1, 1-trichloroethyl or pentafluoroethyl.

A-O- means hydroxy or alkoxy, especially e.g. Methoxy, ethoxy,

Propoxy or butyloxy.

The compounds of the formula I and also the starting materials for their preparation are otherwise prepared by methods which are known per se, as described in the literature (for example in the standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg-Thieme-Verlag, Stuttgart), are described, under reaction conditions that are known and suitable for the reactions mentioned. It is also possible to use variants which are known per se and are not mentioned here in detail.

L in the compounds of the formula II, or L and U in the compounds of the formula V, in each case independently of one another, denotes 01, Br, I or a free or reactive esterified OH group.

If L represents a reactive esterified OH group, this is preferably trichloromethoxy, alkoxy, such as e.g. Methoxy, ethoxy, propoxy or butoxy, further phenoxy, alkylsulfonyloxy with 1-6 C atoms (preferably methylsulfonyloxy) or aryisulfonyloxy with 6-10 C atoms (preferably phenyl- or p-tolylsulfonyloxy, also also 2-naphthalenesulfonyloxy) ). In the compounds of the formula V in particular, L denotes 01 imidazolyl, ethoxy, trichloromethoxy, phenoxy or nitrophenoxy.

If desired, the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture, but instead are immediately reacted further to give the compounds of the formula I. On the other hand, it is possible to carry out the reaction in stages.

The compounds of the formula I can preferably be obtained by reacting compounds of the formula II with compounds of the formula III. Some of the starting materials of formulas II and III are known. If they are not known, they can be produced by methods known per se.

Primary alcohols of the formula. II are e.g. by reducing the corresponding carboxylic acids or their esters. Treatment with thionyl chloride, hydrogen bromide, phosphorus tribromide or similar halogen compounds provides the corresponding halides of the formula II.

3- (4-piperidyl) indoles of the formula III can be prepared, for example, by reacting 4-piperidones with indole or corresponding derivatives substituted by R ² and / or R ^3, followed by acid treatment and hydrogenation.

The reaction of the compounds of formula II with compounds of formula III is usually carried out in an inert solvent, in the presence of an acid-binding agent, preferably an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate or other salt of a weak acid Alkali or alkaline earth metals, preferably of potassium, sodium, calcium or cesium. The addition of an organic base such as triethylamine, dimethylaniline, pyridine or quinoline can also be favorable. Depending on the conditions used, the reaction time is between a few minutes and 14 days, the reaction temperature between about 0 ° and 150 °, normally between 20 ° and 130 °.

Suitable inert solvents are, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; 'glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide or dimethylformamide (DMF); Nitriles like Acetonitrile; Sulfoxides such as dimethyl sulfoxide (DMSO); Carbon disulfide; Carboxylic acids such as formic acid or acetic acid; Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate or mixtures of the solvents mentioned.

Compounds of the formula I can furthermore preferably be obtained by reacting compounds of the formula IV with compounds of the formula V. Suitable compounds of the formula V are preferably dialkyl carbonates such as dimethyl, ditrichloromethyl or diethyl carbonate, chloroformic acid esters such as methyl or ethyl chloroformate, N, N'-carbonyldiimidazole or phosgene.

Some of the starting materials of the formulas IV and V are known. If they are not known, they can be produced using methods known per se. The reaction takes place in solvents and at temperatures as described above.

Compounds of the formula VI can also be reductively converted into compounds of the formula I. It is preferable to use catalytic hydrogenation with e.g. Palladium on activated carbon and hydrogen.

Some of the starting materials of the formula VI are known. If they are not known, they can be produced by methods known per se. The reduction takes place in solvents and at temperatures as described above.

It is also possible to convert a compound of the formula I in which R ^{1 is} OH by alkylation into an ether compound of the formula I in which R ^{1 is} alkoxy.

A base of the formula I can be converted into the associated acid addition salt using an acid, for example by reacting equivalent amounts of the base and the acid in an inert solvent such as ethanol and subsequent evaporation. In particular, acids that contain physiologically acceptable salts are suitable for this implementation. ze deliver. Thus, inorganic acids can be used, for example sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, and also organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carbon, sulfone - or sulfuric acids, e.g. formic acid, acetic acid, propionic acid, pivalic acid, diethyl acetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isoniconic acid sulfonic acid, methonic acid sulfonic acid, methonic acid sulfonic acid, methonic acid sulfonic acid, Ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mono- and disulfonic acids, laurylsulfuric acid. Salts with physiologically unacceptable acids, for example picrates, can be used for the isolation and / or purification of the compounds of the formula I.

Compounds of the formula I according to the invention can be chiral due to their molecular structure and can accordingly occur in two more enantiomeric forms. They can therefore be in racemic or optically active form.

Since the pharmaceutical activity of the racemates or the stereoisomers of the compounds according to the invention can differ, it may be desirable to use the enantiomers. In these cases, the end product or even the intermediates can be separated into enantiomeric compounds by chemical or physical measures known to the person skilled in the art or can already be used as such in the synthesis.

In the case of racemic amines, diastereomers are formed from the mixture by reaction with an optically active release agent. Suitable release agents are, for example, optically active acids, such as the R and S forms of tartaric acid, diacetyl tartaric acid, dibenzoyl tartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (eg N-benzoylproline or N-benzenesulfonylproline) or the various optically active ones Camphorsulfonic acids. Chromatographic separation of enantiomers with the aid of an optically active separation is also advantageous. by means of (eg dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives of carbohydrates or chiral derivatized methacrylate polymers fixed on silica gel). Suitable solvents are aqueous or alcoholic solvent mixtures such as hexane / isopropanol / acetonitrile, for example in a ratio of 82: 15: 3.

Salts with physiologically unacceptable acids, e.g. B. picrates, can be used for the isolation and / or purification of the compounds of formula I.

The invention further relates to the use of the compounds of the formula I and / or their physiologically acceptable salts for the production of pharmaceutical preparations, in particular by a non-chemical route. They can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or auxiliary and, if appropriate, in combination with one or more further active ingredients.

The invention further relates to pharmaceutical preparations containing at least one compound of the formula I and / or one of its physiologically acceptable salts.

These preparations can be used as medicinal products in human or veterinary medicine. Suitable carriers are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical application and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin , Carbohydrates such as lactose or starch, magnesium stearate, talc, petroleum jelly. Tablets, pills, dragees, capsules, powders, granules, syrups, juices or drops are used for oral use, suppositories for rectal use, solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants for topical use for parenteral use Ointments, creams or powder. The new compounds can also be lyophilized and the ones obtained

Lyophilisates can be used, for example, for the production of injectables the. The specified preparations can be sterilized and / or contain auxiliary substances such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, flavoring and / or several other active substances, eg one or more vitamins.

The compounds of the formula I according to the invention are generally administered in analogy to other known preparations which are commercially available for the claimed indications (for example imipramine, fluoxetine, olomipramine), preferably in doses between 0.1 mg and 500 mg, in particular between 5 and 300 mg per dosage unit. The daily dosage is preferably between about 0.01 and 250 mg / kg, in particular between 0.02 and 100 mg / kg body weight.

However, the specific dose for each patient depends on a wide variety of factors, for example on the effectiveness of the particular compound used, on the age, body weight, general health, sex, on the diet, on the time and route of administration, on the rate of elimination and combination of drugs and severity of the respective disease to which the therapy applies. Oral application is preferred.

All temperatures above and below are given in ° C. In the examples below, "customary work-up" means: if necessary, water is added, if necessary, depending on the constitution of the end product, the pH is adjusted to between 2 and 10, extracted with ethyl acetate or dichloromethane, separated, dried organic phase over sodium sulfate, evaporates and purifies by chromatography on silica gel, the isomers described below also being separated and / or by crystallization. Rf values on silica gel; Mobile solvent: ethyl acetate / methanol 9: 1. Mass spectrometry: El (electron impact ionization): M ⁺

FAB (Fast Atom Bombardment): (M + H) ⁺ example 1

A solution of 5- (methanesulfonyloxymethyl) -3-p-methoxyphenyl-oxazol-idin-2-one [obtainable by reacting 2,3-epoxypropanol with N-benzyl-p-methoxyaniline to 1 - (N-benzyl-p- methoxy-anilino-propan-2,3-diol, hydrogenolysis to 1-p-methoxyanilinopropane-2,3-diol, reaction with diethyl carbonate to 5-hydroxymethyl-3-p-methoxyphenyl-oxazolidin-2-one and reaction with CH ₃ SO ₂ CI] in acetonitrile is treated with equimolar amounts of 4- (3-indolyl) piperidine ("A"), potassium iodide and potassium carbonate, heated under reflux for 16 hours and then worked up as usual

3- (4-methoxyphenyl) -5- [4- (3-indolyl) -1-piperidinylmethyl] oxazolidin-2-one, mp 151-153 °.

Analogously, by converting "A"

with (5S) -5- (methanesulfonyloxymethyl) -3-p-methoxyphenyl-oxazolidin-2-one

(5S) - (-) 3- (4-methoxyphenyl) -5- [4- (3-indolyl) -1-ρiperidinylmethyl] - oxazolidin-2-one, hydrochloride, mp 234-236 °, α _D ²⁰ - 56 ° (c = 1, methanol);

with (5S) -5- (methanesulfonyloxymethyl) -3-p-chlorophenyl-oxazolidin-2-one

(5S) - (-) 3- (4-chlorophenyl) -5- [4- (3-indolyl) -1-piperidinylmethyl] - oxazolidin-2-one, mp 188-189 °, α _D ²⁰ -28 ° (c = 1, DMSO); Hydrochloride, mp 260-263 °;

with 5- (methanesulfonyloxymethyl) -3-p-cyanphenyl-oxazolidin-2-one

3- (4-cyanophenyl) -5- [4- (3-indolyl) -1-piperidinylmethyl] oxazolidin-2-one;

with 5- (methanesulfonyloxymethyl) -3-phenyl-oxazolidin-2-one

3-phenyl-5- [4- (3-indolyl) -1-piperidinylmethyl] oxazolidin-2-one;

with 5- (methanesulfonyloxymethyl) -3-p-fluorophenyl-oxazolidin-2-one

3- (4-fluorophenyl) -5- [4- (3-indolyl) -1-piperidinylmethyl] oxazolidin-2-one. Analogously, reaction of 4- (5H-1,3-dioxolo [4,5-f] -indol-7- yl) -piperidine ("B")

with (5S) -5- (methanesulfonyloxymethyl) -3-p-methoxyphenyloxazolidin-2-one (5S) - (-) 3- (4-methoxyphenyl) -5- [4- (5H-1,3-dioxolo [4,5-f] -indol-7-yl) -1- piperidinylmethyl] -oxazolidin-2-one, hydrochloride, mp 232-234 °, α _D ²⁰ -50.5 ° (c = 1, methanol) ;

with (5S) -5- (methanesulfonyloxymethyl) -3-p-chlorophenyloxazolidin-2-one (5S) - (-) 3- (4-chlorophenyl) -5- [4- (5H-1,3-dioxolo [4,5-f] -indol-7-yl) -1-piperidinylmethyl] -oxazolidin-2-one.

Analogously, 4- (5-fluoro-3-indolyl) piperidine ("C") is obtained by reacting

with (5S) -5- (methanesulfonyloxymethyl) -3-p-methoxyphenyloxazolidin-2-one (5S) - (-) 3- (4-methoxyphenyl) -5- [4- (5-fluoro-3-indolyl ) -1-piperidinyl-methyl] -oxazolidin-2-one, hydrochloride, mp 233-234 °, α _D ²⁰ -58.5 ° (c = 1, DMSO);

with 5- (methanesulfonyloxymethyl) -3-p-cyanphenyl-oxazolidin-2-one

3- (4-cyanophenyl) -5- [4- (5-fluoro-3-indolyl) -1-piperidinylmethyl] oxazolidin-2-one, hydrochloride, mp 290-292 °;

with (5S) -5- (methanesulfonyloxymethyl) -3-p-cyanphenyl-oxazolidin-2-one (5S) - (-) 3- (4-cyanophenyl) -5- [4- (5-fluoro-3-indolyl ) -1-piperidinylmethyl] - oxazolidin-2-one, hydrochloride, mp 203-204 °, α _D ²⁰ -36.5 ° (c = 1, DMSO);

with (5R) -5- (methanesulfonyloxymethyl) -3-p-cyanphenyl-oxazolidin-2-one

(5R) - (+) 3- (4-cyanophenyl) -5- [4- (5-fluoro-3-indolyl) -1-piperidinylmethyl] - oxazolidin-2-one, hydrochloride, mp 286-287 °, α _D ²⁰ +41.5 ° (c = 1, DMSO).

Analogously, 4- (5-cyano-3-indolyl) piperidine ("D") is obtained by reacting

with 5- (methanesulfonyloxymethyl) -3-p-cyanphenyl-oxazolidin-2-one

3- (4-cyanophenyl) -5- [4- (5-cyan-3-indolyl) -1-piperidinylmethyl] oxazole-idin-2-one, hydrochloride, mp 290 °; with (5S) -5- (methanesulfonyloxymethyl) -3-p-fluorophenyl-oxazolidin-2-one

(5S) - (-) - 3- (4-fluorophenyl) -5- [4- (5-cyan-3-indolyl) -1-piperidinylmethyl] -oxazolidin-2-one, hydrochloride, m.p. 252- 253 °;

with (5S) -5- (methanesulfonyloxymethyl) -3-p-cyanphenyl-oxazolidin-2-one

(5S) - (-) - 3- (4-cyanophenyl) -5- [4- (5-cyan-3-indolyl) -1-piperidinylmethyl] -oxazolidin-2-one, hydrochloride, F. 270- 271 °, cx _D ²⁰ -38.7 ° (c = 1, DMSO);

with (5R) -5- (methanesulfonyloxymethyl) -3-p-cyanphenyl-oxazolidin-2-one

(5R) - (+) - 3- (4-cyanophenyl) -5- [4- (5-cyan-3-indolyl) -1-piperidinylmethyl] -oxazolidin-2-one, hydrochloride, F. 270- 272 °, _D ²⁰ + 37.7 ° (c = 1,

DMSO);

with 5- (methanesulfonyloxymethyl) -3-p-fluorophenyl-oxazolidin-2-one 3- (4-fluorophenyl) -5- [4- (5-cyan-3-indolyl) -1 -piperidinylmethylj-oxazole-idin-2 -one, hydrochloride, mp 264-268 °;

with 5- (methanesulfonyloxymethyl) -3-phenyl-oxazolidin-2-one 3-phenyl-5- [4- (5-cyan-3-indolyl) -1-piperidinylmethyl] -oxazolidin-2-one, hydrochloride hydrate , Mp 183-185 °;

with (5R) -5- (methanesulfonyloxymethyl) -3-p-fluorophenyl-oxazolidin-2-one (5R) - (+) - 3- (4-fluorophenyl) -5- [4- (5-cyan-3- indolyl) -1-piperidinylmethyl] -oxazolidin-2-one, hydrochloride, mp 184-188 °, α _D ²⁰ + 27.2 ° (c = 1,

DMSO),

Analogously, 4- (6-fluoro-3-indolyl) piperidine ("E") is obtained by reacting

with (5S) -5- (methanesulfonyloxymethyl) -3-p-cyanophenyl-oxazolidin-2-one (5S) - (-) - 3- (4-cyanophenyl) -5- [4- (6-fluoro-3- indolyl) -1-piperidinylmethyl] - oxazolidin-2-one, hydrochloride, mp 287-288 °, α _D ²⁰ -38.4 ° (c = 1, DMSO);

with 5- (methanesulfonyloxymethyl) -3-p-fluorophenyl-oxazolidin-2-one

3- (4-fluorophenyl) -5- [4- (6-fluoro-3-indolyl) -1-piperidinylmethyl] oxazole-idin-2-one, hydrochloride, mp 257-259 °; with (5R) -5- (methanesulfonyloxymethyl) -3-p-cyanphenyl-oxazolidin-2-one

(5R) - (+) - 3- (4-cyanophenyl) -5- [4- (6-fluoro-3-indolyl) -1-piperidinylmethyl] -oxazolidin-2-one, hydrochloride, F. 288- 290 °, α _D ²⁰ + 38.8 ° (c = 1, DMSO);

with 5- (methanesulfonyloxymethyl) -3-phenyl-oxazolidin-2-one

3-phenyl-5- [4- (6-fluoro-3-indolyl) -1-piperidinylmethyl] oxazolidin-2-one, hydrochloride, mp 234-236 °.

Example 2

A solution of 1- [4- (3-indolyl) piperidin-1-yl] -3- (4-methoxy-anilino) propan-2-ol in dichloromethane is mixed with equimolar amounts of di-trichloromethyl carbonate and 5 Hours stirred. After customary working up, 3- (4-methoxyphenyl) -5- [4- (3-indolyl) -1-piperidinylmethyl] -oxazolidin-2-one, mp 151-153 °, is obtained.

Example 3

With a solution of 5- [4- (3-indolyl) -3,6-dihydro-2H-pyridin-1-ylmethyl] -3- (4-methoxyphenyl) oxazolidin-2-one [obtainable by dehydrating 3- (4-methoxyphenyl) -5- [4- (3-indolyl) -4-hydroxy-1-piperidinylmethyl] - oxazolidin-2-one, which is obtained by reaction of 3- (4-methoxyphenyl) -5- [4- oxo -1 -piperidinylmethyl] -oxazolidin-2-one was prepared with indole] in methanol, hydrogen is passed in the presence of palladium (10% on activated carbon) for 1 hour. After removal of the catalyst and customary work-up, 3- (4-methoxyphenyl) -5- [4- (3-indolyl) -1-piperidinyl-methylJ-oxazolidin-2-one, mp 151-153 °.

The following examples relate to pharmaceutical preparations:

Example A: Injection glasses

A solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogenphosphate is adjusted to pH 6.5 in 3 l of double-distilled water with 2N hydrochloric acid, sterile filtered, filled into injection glasses, lyophilized under sterile conditions and sealed sterile. Each injection jar contains 5 mg of active ingredient.

Example B: Suppositories

A mixture of 20 g of an active ingredient of the formula I is melted with 100 g of soy lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.

Example C: solution

A solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g of NaH ₂ PO ₄ 2H ₂ O, 28.48 g of Na ₂ HPO ₄ 12H ₂ O and 0.1 g of benzalkonium chloride in 940 ml of double-distilled water. Adjust to pH 6.8, fill to 1 | on and sterilized by radiation.

Example D: ointment

500 mg of an active ingredient of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.

Example E: tablets

A mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed into tablets in a conventional manner such that each tablet contains 10 mg of active ingredient.

Example F: coated tablets

Analogously to Example E, tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant. Example G: capsules

2 kg of active ingredient of the formula I are filled into hard gelatin capsules in a conventional manner, so that each capsule contains 20 mg of the active ingredient.

Example H: ampoules

A solution of 1 kg of active ingredient of the formula I in 60 l of double-distilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed sterile. Each ampoule contains 10 mg of active ingredient.

Claims

claims

1. Compounds of formula I.

wherein

R ¹ H, CN, shark or OA,

R ² , R ³ each independently of one another are H, CN, shark or OA,

R ² and R ³ together also methylenedioxy,

AH, CF ₃ or alkyl with 1-6 C atoms and

Shark F, Cl, Br, I mean, and their salts.

2. Enantiomers of the compounds of formula I according to claim 1.

3. Compounds of formula I according to claims 1 or 2

a) (5S) - (-) - 3- (4-chlorophenyl) -5- [4- (3-indolyl) -1-piperidinylmethyl] - oxazolidin-2-one;

b) 3- (4-cyanophenyl) -5- [4- (5-cyan-3-indolyl) -1-piperidinylmethyl] oxazolidin-2-one;

c) (5S) - (-) - 3- (4-Cyanρhenyl) -5- [4- (6-fluoro-3-indolyl) -1-piperidinylmethyl] -oxazolidin-2-one;

d) (5R) - (+) - 3- (4-cyanophenyl) -5- [4- (5-fluoro-3-indolyl) -1-piperidinylmethyl] oxazolidin-2-one; e) (5R) - (+) - 3- (4-cyanophenyl) -5- [4- (6-fluoro-3-indolyl) -1-piperidinylmethyl] -oxazolidin-2-one;

f) 3-phenyl-5- [4- (5-cyan-3-indolyl) -1-piperidinyl-methyl] -oxazolidin-2-one;

g) 3-phenyl-5- [4- (6-fluoro-3-indolyl) -1-piperidinyl-methyl] -oxazolidin-2-one;

as well as their salts.

4. A process for the preparation of compounds of formula I according to claim 1, characterized in that

a) a compound of formula II

in which R ^{1 has} the meaning given in claim 1 and L is Cl, Br, I or a free or reactively functionally modified OH group,

with a compound of formula III

wherein R ² and R ^{3 have} the meanings given in claim 1,

implements or

b) a compound of formula IV

in which R ¹ , R ² and R ^{3 have} the meanings given in claim 1,

with a compound of formula V

implements

or

c) a compound of formula VI

in which R ¹ , R ² and R ^{3 have} the meanings given in claim 1, hydrated,

5. A process for the preparation of pharmaceutical preparations, characterized in that a compound of formula I according to claim 1 and / or one of its physiologically tolerable salts or one of its enantiomers together with at least one solid, liquid or semi-liquid carrier or auxiliary and, if appropriate, in combination with one or more other active ingredients in a suitable dosage form.

6. Pharmaceutical preparation, characterized by a content of at least one compound according to one of claims 1 or 2 and / or one of its physiologically acceptable salts.

7. Compounds of formula I according to claim 1 and their physiologically acceptable salts for combating the consequences of stroke and cerebral ischemia, for the treatment of obsessive-compulsive behavior

(OCD), anxiety, panic attacks, depression, psychosis, schizophrenia and Parkinson's disease.

8. Medicament of formula I according to claim 1 and its physiologically _acceptable salts as 5-HT _2Λ antagonists with 5-HT reuptake-inhibiting effect.

9. Use of compounds of formula I according to claim 1 and / or their physiologically acceptable salts for the manufacture of a medicament.

10. Use of compounds of formula I according to claim 1 and / or their physiologically acceptable salts in combating the consequences of stroke and cerebral ischemia, for the treatment of obsessive-compulsive behavior (OCD), anxiety, panic attacks. depression, psychosis, schizophrenia and Parkinson's disease.